When the stomach is empty, ghrelin is secreted. When the stomach is stretched, secretion stops.a It acts on hypothalamic brain cells both to increase hunger, and to increase gastric acid secretion and gastrointestinal motility to prepare the body for food intake.[5]

History and name

Ghrelin was discovered after the ghrelin receptor (called growth hormone secretagogue type 1A receptor or GHS-R) was discovered in 1996[11] and was reported in 1999.[12] The hormone name is based on its role as a growth hormone-releasing peptide, with reference to the Proto-Indo-European root gʰre-, meaning "to grow".[13]

Gene, transcription products, and structure

Preproghrelin (green and blue) and ghrelin (green).

The GHRL gene produces mRNA which has four exons. Five products arise: the first is the 117-amino acid preproghrelin. (It is homologous to promotilin; both are members of the motilin family). It is cleaved to produce proghrelin which is cleaved to produce a 28-amino acid ghrelin (unacylated) and C-ghrelin(acylated). Obestatin is presumed to be cleaved from C-ghrelin.[14]

Ghrelin only becomes active when caprylic (octanoic) acid is linked posttranslationally to serine at the 3-position by the enzyme ghrelin O-acyltransferase (GOAT). It is located on the cell membrane of ghrelin cells in the stomach and pancreas.[15] The non-octanoylated form is desacyl ghrelin. It does not activate the GHS-R receptor but does have other effects: cardiac,[16] anti-ghrelin,[17] appetite stimulation,[18] and inhibition of hepatic glucose output[19]. Side-chains other than octanoyl have also been observed: these can also trigger the ghrelin receptor.[20] In particular, decanoyl ghrelin has been found to constitute a significant portion of circulating ghrelin in mice, but as of 2011 its presence in humans has not been established.[21]

Location

Ghrelin cells are found mainly in the stomach[23] and duodenum, but also in the jejunum, lungs, pancreatic islets,[24] gonads, adrenal cortex, placenta, and kidney. It has recently been shown that ghrelin is produced locally in the brain[25]

Features

Ghrelin cells are found in oxyntic glands (20% of cells),[26] pyloric glands, and small intestine.
They are ovoid cells with granules.[27] They have gastrin receptors.[28] Some produce nesfatin-1.[29] Ghrelin cells are not terminally differentiated in the pancreas: they are progenitor cells that can give rise to A-cells, PP cells and Beta-cells there.[30]

Function and mechanism of action

Ghrelin is a participant in regulating the complex process of energy homeostasis which adjusts both energy input – by adjusting hunger signals – and energy output – by adjusting the proportion of energy going to ATP production, fat storage, glycogen storage, and short-term heat loss. The net result of these processes is reflected in body weight, and is under continuous monitoring and adjustment based on metabolic signals and needs. At any given moment in time, it may be in equilibrium or disequilibrium. Gastric-brain communication is an essential part of energy homeostasis, and several communication pathways are probable, including the gastric intracellular mTOR/S6K1 pathway mediating the interaction among ghrelin, nesfatin and endocannabinoid gastric systems,[31] and both afferent and efferent vagal signals.

In addition to its function in energy homeostasis, ghrelin also activates the cholinergic–dopaminergic reward link in inputs to the ventral tegmental area and in the mesolimbic pathway,[7] a circuit that communicates the hedonic and reinforcing aspects of natural rewards,[3] such as food and addictive drugs such as ethanol.[39][41][42] Ghrelin receptors are located on neurons in this circuit.[3][8] Hypothalamic ghrelin signalling is required for reward from alcohol[43] and palatable/rewarding foods.[44][45]

Ghrelin has been linked to inducing appetite and feeding behaviors. Circulating ghrelin levels are the highest right before a meal and the lowest right after.[46][47] Injections of ghrelin in both humans and rats have been shown to increase food intake in a dose-dependent manner.[48] So the more ghrelin that is injected the more food that is consumed. However, ghrelin does not increase meal size, only meal number.[49] Ghrelin injections also increase an animal's motivation to seek out food, behaviors including increased sniffing, foraging for food, and hoarding food. Body weight is regulated through energy balance, the amount of energy taken in versus the amount of energy expended over an extended period of time. Studies have shown that ghrelin levels are negatively correlated with weight. This data suggests that ghrelin functions as an adiposity signal, a messenger between the body's energy stores and the brain.[5]

Blood levels

Blood levels are in the pmol/l range. Both active and total ghrelin can be measured.[50] Circulating ghrelin concentrations rise before eating and fall afterward,[46] more strongly in response to protein and carbohydrate than to lipids.[21]

Ghrelin receptor

The ghrelin receptor GHS-R1a (a splice-variant of the growth hormone secretagogue receptor, with the GHS-R1b splice being inactive) is involved in mediating a wide variety of biological effects of ghrelin, including: stimulation of growth hormone release, increase in hunger, modulation of glucose and lipid metabolism, regulation of gastrointestinal motility and secretion, protection of neuronal and cardiovascular cells, and regulation of immune function.[51] They are present in high density in the hypothalamus and pituitary, on the vagus nerve (on both afferent cell bodies and efferent nerve endings) and throughout the gastrointestinal tract.[15][40]

Locations of action

Pancreas

Ghrelin inhibits glucose-stimulated insulin secretion from beta cells in the pancreatic islets. Ghrelin does this indirectly by promoting local negative feedback mediated by somatostatin from pancreatic delta cells, which selectively express the ghrelin receptor.[52]

Glucose metabolism

The entire ghrelin system (dAG, AG, GHS-R and GOAT) has a gluco-regulatory action.[53]

Nervous system

Learning and memory

The hippocampus plays a significant role in neurotrophy: the cognitive adaptation to changing environments and the process of learning[54][55] and it is a potent stimulator of growth hormone.[12]Animal models indicate that ghrelin may enter the hippocampus from the bloodstream, altering nerve-cellconnections, and so altering learning and memory.[56] It is suggested that learning may be best during the day and when the stomach is empty, since ghrelin levels are higher at these times. A similar effect on human memory performance is possible.[54] In rodents, X/A-like cells produce ghrelin.[57]

Ghrelin has been shown to have implications for depression prevention. Antidepressant-like attributes were demonstrated when mice with high levels of ghrelin and mice with the ghrelin gene knocked out underwent social defeat stress and then were placed in the forced swim tank. Mice with elevated ghrelin swam more than ghrelin deficient mice.[59] These ghrelin-deficient mice exhibited more social avoidance as well. These mice did not exhibit depression-like behaviors when injected with a commonly prescribed antidepressant, suggesting that ghrelin acts as a short-term natural adaptation against depression.

Sleep duration

Short sleep duration is associated with high levels of ghrelin and obesity. An inverse relationship between the hours of sleep and blood plasma concentrations of ghrelin exists; as the hours of sleep increase, ghrelin levels trend lower and obesity is less likely.[60]

Stress-induced fear

Prior stress exposure heightens fear learning during Pavlovian fear conditioning. Stress-related increases in ghrelin circulation were shown to be necessary and sufficient for stress to increase fear learning. Ghrelin was found to be upregulated by stress even in the absence of adrenal hormones. Blocking the ghrelin receptor during stress abolished stress-related enhancement of fear memory without blunting other markers of stress. These results suggest that ghrelin is a novel branch of the stress response.[61] Human studies are needed to translate the use of anti-ghrelin treatments to prevent stress-induced psychiatric disorders.

Reproductive system

Fetus and neonate

Ghrelin is produced early by the fetal lung and promotes lung growth.[64]

Cord blood levels of active and total ghrelin show a correlation between ghrelin levels and birth weight.[50]

Anorexia and obesity

Ghrelin levels in the plasma of obese individuals are lower than those in leaner individuals,[65] suggesting that ghrelin does not contribute to obesity, except in the cases of Prader-Willi syndrome-induced obesity, where high ghrelin levels are correlated with increased food intake.[66][67] However, it is also found that consumption of food for pleasure increased peripheral levels of both ghrelin and the endocannabinoid2-arachidonoyl-glycerol (2-AG) in healthy humans, and this hedonic eating influences food intake and, ultimately, body mass.[68]

Those with anorexia nervosa have high plasma levels of ghrelin[69] compared to both the constitutionally thin and normal-weight controls.[70][71]

The level of ghrelin increases during the time of day from midnight to dawn in thinner people, which suggests there is a flaw in the circadian rhythm of obese individuals.[72]

Ghrelin levels reflect release in a circadian rhythm, which can be interrupted by exposure to light at night.[73]

Short sleep duration may also lead to obesity, through an increase of appetite via hormonal changes.[74]

Lack of sleep increases ghrelin and decreases leptin, both of which result in increased hunger and obesity.

Disease management

Gastric bypass surgery

Gastric bypass surgery not only reduces the gut's capacity for food but also dramatically lowers ghrelin levels compared to both lean controls and those that lost weight through dieting alone.[76] However, studies are conflicting as to whether or not ghrelin levels return to nearly normal with gastric bypass patients in the long term after weight loss has stabilized.[77] Bariatric surgeries involving vertical-sleeve gastrectomy reduce plasma ghrelin levels by about 60% in the long term.[78]

Aging

Ghrelin plasma concentration increases with age and this may contribute to the tendency for weight gain as people age.[79][80]

Future clinical uses

Synthetic ghrelin administration for cachexia of any cause[81] and for hemodialysis patients[82] is being investigated.

See also

Notes

Template:Note It is important to note that the full mechanism of ghrelin secretion and reduction has not been fully realized, e.g. "this finding appears to discount gastric distention as a mechanism for ghrelin reduction".[85]